The basic concept of cellular therapy has been known since the time of Paracelsus, who in the 16th Century stated “Heart heals the heart, lung heals lung, spleen heals spleen; like cures like.” These philosophical ponderings of this alchemist were reduced to practice by the controversial Swiss physician Paul Niehans who utilized fetal xenogeneic cells to treat a variety of ailments in the early part of the last century. In recent times cell therapy has been gaining momentum for treatment of a wide variety of disorders. By far the most widely established use of cell therapy is for treatment of leukemias in the form of bone marrow transplantation.
The first hematopoietic stem cell transplant, or bone marrow transplant, was performed in 1956 by Dr. E. Donnall Thomas using bone marrow cells isolated from an identical twin donor for a recipient who had leukemia. The idea was that if the patient was irradiated with high doses, then the radiation would kill all of the leukemia cells. Unfortunately, the radiation would also destroy the healthy bone marrow stem cells. So the idea was to utilize donor bone marrow to replenish the recipient with healthy hematopoietic stem cells. Dr. Thomas, along with Joseph E. Murray, won the Nobel Prize in 1990 for this discovery.
As described above, transfer of bone marrow stem cells has been performed for decades. Scientists have wondered if the bone marrow stem cell possesses the potential to differentiate into all the different types of blood cells, maybe it can also differentiate into other cells as well. This process was originally termed “transdifferentiation”. The first report of transdifferentiation to appear in the major medical literature was a paper by Orlic et al. [1], in which mouse bone marrow derived stem cells were injected into mice that were given an experimental heart attack. The interesting thing about this experiment was that the bone marrow stem cells used were labeled to glow green. The donor animals were genetically engineered to express the green fluorescent protein (GFP) gene throughout their bodies. This essentially means that all cells derived from the GFP donor mice were green. Additionally, the experimenters purified the mouse equivalent of the human CD34 bone marrow hematopoietic stem cell. The molecular markers used where positivity for stem cell antigen (SCA-1) and negativity for the lineage markers (lin negative). Following induction of a heart attack by ligation of one of the coronary arteries, the researchers implanted the cells in the area of infarct. The mice which received implanted hematopoietic stem cells, but not control cells, had increased pumping ability of the heart and decreased levels of heart damage.
Numerous other experiments have demonstrated efficacy of cell therapy in animals and humans for non-hematopoietic purposes. For example Japanese researchers have demonstrated that when bone marrow cells are injected into the heart muscle of patients undergoing bypass surgery a therapeutic effect is observed. The idea was that the injected bone marrow cells will stimulate production of new blood vessels and thereby increase oxygenation to the heart [2]. The procedure, although highly invasive, was associated with no treatment related adverse effects and 3 out of the 5 patients had increased blood vessel production as assessed radiologically, as well as improved cardiac function. This first demonstration in 2001, was repeated by numerous investigators. In 2003, the study was repeated using CD133 purified bone marrow stem cells and published in the prestigious journal Lancet [3], reporting positive results. Subsequently numerous studies have been conducted in the area of cardiology demonstrating that administration of a patient's own bone marrow is associated with positive outcome. Another example of cell therapy was a program conducted by Layton Biosciences, who developed a homogeneous cellular population by differentiating a proprietary teratocarcinoma cell line into neurons using a retinoic acid based protocol. These cells, called LBS-neurons were utilized in several clinical trials. In one trial surgical implantation of these cells was demonstrated to induce improvement based on the functional ESS score in some patients [4].
Cell therapy has also been used in the treatment of diabetes, for example, the Edmonton Protocol involves intrahepatic administration of donor islets under the cover of calcineurin-sparing immune suppressants. This approach has resulted in reduced insulin requirements of Type I diabetics, and in some cases achievement of complete insulin independence [5, 6]. Other uses of cell therapy include treatment of stroke [7], liver failure [8], lung failure [9], and peripheral artery disease [10].
The use of cell therapy for immune modulation has been conducted primarily in terms of immune stimulation, as is the case of Provenge, the FDA approved therapeutic vaccine for prostate cancer. Unfortunately, the use of cell therapy for tolerance induction has not been performed in an applicable manner that is commercially relevant.